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Design & Synthesis of Protein Interacting Affinity Ligands and Protease Inhibitors
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Hans Adolfsson)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is a growing need of both protein drugs and synthetic drugs in the fight against many life-threatening diseases. The first part of this thesis deals with the design and synthesis of high affinity binding ligands for the purification of protein drugs. The second part describes design and synthesis of protease inhibitors targeting the cysteine protease cathepsin S and the serine protease hepatitis C NS3/4A.

In work with parallel synthesis of new affinity chromatography ligands, indole was used as the scaffold for both solid phase and solution phase syntheses. A library of 1,3-disubstituted indoles was prepared via an iterative Mannich reaction sequence. The first Mannich reaction provided 3-aminomethylindoles, while the second Mannich reaction introduced an additional aminomethyl group at the N1 position of the indole ring. A library of 25 substituted indoles was prepared in moderate to good yields and purity.

Inhibition of the cysteine protease cathepsin S is an attractive target for drug development of inhibitors having potential for regulation of autoimmune diseases and allergic disorders. Syntheses targeting the cysteine protease cathepsin S were performed by a solid phase approach. The structure-activity-relationships (SAR) of variations in the P3 sulfonamide part of 4-amidofuran-3-one inhibitors are presented. Several highly potent inhibitors were found, in both enzyme and cellular assays.

The hepatitis C virus (HCV), causes a chronic liver condition which can lead to cirrhosis and liver cancer. The  serine protease hepatitis C NS3/4A is a promising target for development of HCV drugs. In the syntheses of novel HCV NS3/4A inhibitors, four new P2 substituents were first incorporated on a proline-based linear scaffold. The most potent P2 substituent, quinazoline, was evaluated in a larger study yielding more rigidified cyclopentane-based macrocyclic inhibitors. The SAR exercise resulted in several inhibitors with excellent potency in the low nanomolar range.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2010. , 96 p.
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-35292ISBN: 978-91-7155-994-4 (print)OAI: oai:DiVA.org:su-35292DiVA: diva2:286921
Public defence
2010-02-11, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: ManuscriptAvailable from: 2010-01-20 Created: 2010-01-15 Last updated: 2010-01-15Bibliographically approved
List of papers
1. Microwave-Assisted Coupling of Carboxylic Acids to a Polymer Bound Hydrazine Linker
Open this publication in new window or tab >>Microwave-Assisted Coupling of Carboxylic Acids to a Polymer Bound Hydrazine Linker
2003 (English)In: Synthetic Communications, ISSN 0039-7911, E-ISSN 1532-2432, Vol. 33, no 13, 2257-2262 p.Article in journal (Refereed) Published
Abstract [en]

A set of carboxylic acids, all being potential scaffolds for combinatorial chemistry or peptide synthesis, were coupled to a polymer bound aryl hydrazine linker using microwave irradiation in good yields. Improved yields and reduced reaction times were achieved byusing microwave-assisted heating compared to conventional heating.

Place, publisher, year, edition, pages
New York: Marcel Dekker, Inc., 2003
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-35061 (URN)
Available from: 2010-01-15 Created: 2010-01-14 Last updated: 2017-12-12Bibliographically approved
2. Parallel synthesis of an indole-based library via an iterativeMannich reaction sequence
Open this publication in new window or tab >>Parallel synthesis of an indole-based library via an iterativeMannich reaction sequence
2006 (English)In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 62, no 14, 3439-3445 p.Article in journal (Refereed) Published
Abstract [en]

A library of 1,3-disubstituted indoles has been prepared via an iterative Mannich reaction sequence. The first Mannich reaction with secondary amines and formaldehyde preferentially yields 3-aminomethyl indoles, while the second Mannich reaction introduces an additional aminomethyl group at the N1-position of the indole ring. A library of 25 substituted indoles has thus been prepared in moderate to good yields with purity.

Place, publisher, year, edition, pages
Elsevier Ltd., 2006
Keyword
Library synthesis, Mannich reaction, Affinity ligands
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-35081 (URN)10.1016/j.tet.2006.01.047 (DOI)
Available from: 2010-01-15 Created: 2010-01-14 Last updated: 2017-12-12Bibliographically approved
3. Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: Effect of sulfonamides P3 substituents on potency and selectivity.
Open this publication in new window or tab >>Solid-phase parallel synthesis and SAR of 4-amidofuran-3-one inhibitors of cathepsin S: Effect of sulfonamides P3 substituents on potency and selectivity.
Show others...
2009 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 17, no 3, 1307-1324 p.Article in journal (Refereed) Published
Abstract [en]

Highly potent and selective 4-amidofuran-3-one inhibitors of cathepsin S are described. The synthesis and structure–activity relationship of a series of inhibitors with a sulfonamide moiety in the P3 position is presented. Several members of the series show sub-nanomolar inhibition of the target enzyme as well as an excellent selectivity profile and good cellular potency. Molecular modeling of the most interesting inhibitors describes interactions in the extended S3 pocket and explains the observed selectivity towards cathepsin K.

Place, publisher, year, edition, pages
Elsevier, 2009
Keyword
Cysteine protease, cathepsin S, cathepsin K, reversible covalent inhibition
National Category
Medicinal Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-35087 (URN)10.1016/j.bmc.2008.12.020 (DOI)
Available from: 2010-01-15 Created: 2010-01-14 Last updated: 2017-12-12Bibliographically approved
4. Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: exploration of P2 quinazoline substituents.
Open this publication in new window or tab >>Synthesis and SAR of potent inhibitors of the Hepatitis C virus NS3/4A protease: exploration of P2 quinazoline substituents.
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Novel NS3/4A protease inhibitors comprising quinazoline derivatives as P2 substituent were synthesized. High potency inhibitors displaying advantageous PK properties have been obtained through the optimization of quinazoline P2 substituents in three series of macrocyclic P2 cyclopentane dicarboxylic acid and P2 proline urea motifs. For the quinazoline moiety it was found that 8-methyl substitution for the P2 cyclopentane dicarboxylic acid series improved on the stability in human liver microsomes. By comparison, the proline urea series displayed advantageous Caco-2 permeability over the cyclopentane series. properties were assessed in rat on selected compounds. Excellent exposure and liver–to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series. In vivo pharmacokinetic properties were assessed in rat on selected compounds. Excellent exposure and liver–to-plasma ratios were demonstrated for a member of the 14-membered quinazoline substituted P2 proline urea series.

National Category
Medicinal Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-35094 (URN)
Available from: 2010-01-15 Created: 2010-01-14 Last updated: 2016-01-29Bibliographically approved

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